GPX2 overexpression is involved in cell proliferation and prognosis of castration-resistant prostate cancer
GPX2 overexpression is involved in cell proliferation and prognosis of castration-resistant prostate cancer
复制标题
DOI：
10.1093/carcin/bgu048
复制
发表时间：
2014-09-01
期刊：
影响因子：
4.7
通讯作者：
Takahashi, Satoru
中科院分区：
文献类型：
--
作者：
Naiki, Taku;Naiki-Ito, Aya;Takahashi, Satoru
有必要探索新的治疗策略，目标去势抵抗性前列腺癌（CRPC）的不同分子机制，因为它的出现后，雄激素剥夺治疗是一个主要的临床问题。在本报告中，我们研究了谷胱甘肽过氧化物酶2（GPX 2）在CRPC中的作用。在大鼠和人CRPC细胞中分析GPX 2表达。接下来，我们测定了GPX 2-小干扰RNA（siRNA）转染的CRPC细胞中的增殖速率和活性氧（ROS）水平。对于体内分析，将siRNA转染的细胞皮下植入正常和去势的裸鼠中。此外，GPX 2的免疫组织化学和预后分析使用人类标本进行。GPX 2的沉默在大鼠（PCai 1）和人（PC 3）CRPC细胞中均引起显著的生长抑制和细胞内ROS增加。流式细胞术和western blot分析显示GPX 2沉默的细胞增殖率下降是由于细胞周期蛋白B1依赖的G（2）/M阻滞。此外，敲低Gpx 2抑制去势小鼠中PCai 1细胞的肿瘤生长。免疫组化分析表明，GPX 2的表达显着较高的残留癌灶后，新辅助激素治疗比激素初治癌灶。此外，在活检标本中GPX 2高表达的患者的前列腺特异性抗原无复发生存率和总生存率显著低于GPX 2无表达的患者。这些发现表明GPX 2是CRPC的预后标志物，并且部分通过保护免受ROS信号传导影响雄激素耗竭下的前列腺癌增殖。
There is a need for exploration of new therapeutic strategies that target distinct molecular mechanisms of castration-resistant prostate cancer (CRPC) because its emergence following androgen deprivation therapy is a major clinical problem. In this report, we investigated the role of glutathione peroxidase 2 (GPX2) in CRPC. GPX2 expression was analyzed in rat and human CRPC cells. Next, we determined the proliferation rate and level of reactive oxygen species (ROS) in GPX2-small interfering RNA (siRNA)transfected CRPC cells. For in vivo analysis, siRNA-transfected cells were subcutaneously implanted into normal and castrated nude mice. Further, immunohistochemical and prognostic analyses of GPX2 were performed using human specimens. Silencing of GPX2 caused significant growth inhibition and increased intracellular ROS in both rat (PCai1) and human (PC3) CRPC cells. Flow cytometry and western blot analyses revealed that the decrease in proliferation rate of the GPX2-silenced cells was due to cyclin B1-dependent G(2)/M arrest. Furthermore, knockdown of Gpx2 inhibited tumor growth of PCai1 cells in castrated mice. Immunohistochemical analyses indicated that expression of GPX2 was significantly higher in residual cancer foci after neoadjuvant hormonal therapy than in hormone naive cancer foci. Moreover, patients with high GPX2 expression in biopsy specimen had significantly lower prostate-specific antigen recurrence-free survival and overall survival than those with no GPX2 expression. These findings suggest that GPX2 is a prognostic marker in CRPC and affects proliferation of prostate cancer under androgen depletion partially through protection against ROS signaling.